Follicular non-Hodgkin's lymphoma is the most common indolent histologic subtype of lymphoma. With the exception of rare localized tumors, FL is thought not to be curable with standard therapeutic approaches;while most patients respond to treatment, relapses are the rule, and many patients will eventually die of their lymphoma. Standard treatment approaches have traditionally relied on combination chemotherapy, but this carries with it significant toxicities. Recently, interest has grown in development of non-chemotherapy approaches to FL treatment. Radioimmunotherapy (RIT) involves the conjugation of a radionuclide with a monoclonal antibody, allowing delivery of radiation based not on location of the lymphoma, as with external beam radiotherapy, but on expression of a cell-surface protein against which the RIT is targeted. The utility of RIT agents currently approved for use in recurrent indolent B cell NHL has been limited by two major factors, including immunogenicity of the antibody and limitations of delivered radiation dose related to the treatment protocol. Recent studies have highlighted the concept that administration of unlabeled and radiolabeled antibodies targeting the same antigen can cause suboptimal radiation targeting (due to competitive binding). The proposed study will explore a novel approach to RIT which optimizes radiation dose delivery to tumor (through use of unlabeled and radiolabeled agents targeting different antigens, CD20 and CD22 respectively) and minimizes immunogenicity (through humanization) by pursuing the following Specific Aims: 1) Determine the biodistribution, tumor localization and pharmacokinetics of radiolabeled epratuzumab therapy and determine any changes in targeting due to pretreatment with veltuzumab, and 2) Establish the safety and efficacy of fractionated 90Y-epratuzumab tetraxetan (anti-CD22) given in combination with veltuzumab (anti- CD20) in patients with previously untreated, intermediate or high risk FL. We anticipate that our approach will provide highly effective, tolerable treatment without use of chemotherapy, even in high risk patients. The modifications of RIT explored in this proposal could impact similar approaches in a broader context, including other histologies of lymphoma as well as other malignancies in which RIT is being explored. PUBLIC HEALTH RELEVANCE: Despite the availability of multiple therapeutic modalities and a high response rate to initial therapy, most patients with follicular lymphoma (FL) will develop recurrent or refractory disease and many will ultimately die from lymphoma-related complications. We propose to study a non-chemotherapeutic approach to initial therapy of FL involving a novel strategy of radioimmunotherapy (RIT) which addresses problems of radiation dose delivery and immunogenicity which have limited utility of previous RIT strategies. This novel approach has implications for optimization of similar approaches in other cancers.